Report On Adverse Reactions Analysis Of Azathioprine In The Treatment Of 364 Patients With Inflammatory Bowel Disease

Research Background:Azathioprine is formed by methylimidazole relacing the hydrogen and sulfur atoms of 6-mercaptopurine(6-MP).Azathioprine is a kind of antimetabolites which has an immunosuppressive action. It can produce alkylate to block SH group, suppress the biosynthesis of nucleic acid, prevent cell proliferation and cause damage to DNA. Animal experiments confirmed that this drug can reduce the DNA and RNA in thymus and spleen, affect the synthesis of DNA, RNA and protein. It can suppress the T-cell to affect the immune function, mainly used in anti-rejection after organ transplantation and treatment of autoimmune diseases.Inflammatory bowel disease (a kind of chronic nonspecific intestinal inflammatory diseases) includes crohn’s disease and ulcerative colitis, which is caused by the hyperactive immune system, but its pathogen is still unknown and not very clear. It’s quite common in Europe, North America, Japan and other developed countries. Though we don’t have the epidemiological data of the public, the number of patients has been increasing in the last decade, so Inflammatory bowel disease has already become a common digestive system disease. Drugs which can suppress the immune system are used to control this disease. Azathioprine is a popular immunosuppressor to cure the inflammatory bowel disease. To play variable biological effects, it’s accomplished by changing into the active 6-Thioguanosine nucleotide(6-TGN). The 6-TGN in cells can suppress the immunoreaction by control the DNA biosynthesis and T cell proliferation.Azathioprine can suppress the biosynthesis of nucleic acid and prevent the cell proliferation. The immunosuppressor will inevitably cause some side effects while it plays its role, including bone marrow inhibition, liver function damage, infection, gastro-intestinal reaction, allergic reaction and so on. We also find that the side effects have a lot to do with the patients, and thiopurine methyltransferase (TPMT) is closely related to the efficacy and side effects. Both thegene mutation of TPMT and the abnormity of enzymatic activity determine the individual effects of drug efficacy and drug toxicity.The clinical experience these years tell us the azathioprine plays a leading role in the treatment of inflammatory bowel disease, however we have to face its side effects in our clinic treatment. Therefore, we need a report on adverse reaction of AZA based on a larger sample to summarize different adverse reactions, classification, correlated monitor, prevention, treatment and prognosis. It will help clinician to use the azathioprine more effectively and safely.Objective:The number of inflammatory bowel disease patients has been rising every year, and new drugs appear all around the world. Although the azathioprine plays an important role in the treatment of inflammatory bowel disease, the clinicians are always thinking about its side effects. So, we are focusing on how to play its drug efficacy and avoid its adverse reactions. This research includes retrospective analysis of patients with IBD in Sir Run Run Shaw Hospital and it’s used to assess the adverse reactions, treatment measures and prognosis of patients with IBD who take the AZA.Methods:This project adopts retrospective study method, and analyzed 364 cases of IBD patients with azathioprine treatment who were treated in Digestive department in Sir Run Run Shaw Hospital from December,1994 to September,2015. It included looking up the medical records and telephoning the follow-up, then we did the analysis of clinical data, the AZA drug, adverse reactions and disease outcome. We adopted T test and chi-square test and other statistical methods to analyze the risk factors resulted in Adverse reaction and leukopenia disease.Results:The average starting dosage of the 364 IBD patients was 48.3 mg/d(25 mg/d-75 mg/d), the average medication time was 11.9 months (5 days-96 months). Most patients took the hormone or biological agent(Infliximab) or 5-aminosalicylic acid(5-ASA) at the same time. Some chose both the hormone/biological agent(Infliximab) and 5-aminosalicylic acid(5-ASA). We observed 178 adverse events in 147 patients(40.4% among all the patients), including myelotoxicity(74), abnormal liver function(31), gastrointestinal reaction(18), infection(14),arthralgia(11). Other 30 adverse events included pancreatitis, dizziness, headache, tetter, alopecia, fever and so on.42.1% of the adverse reaction(75/178) occurred during the first month of therapy. Withdrawal of drug occurred in 20.1% patients(73/364) because of side effects.52.1% of these patients(38/73) withdraw the drug in the first month of therapy. The incident of leukopenia in patients who add 5-ASA was higher than single AZA, The incident of leukopenia and adverse reaction in patients treated with AZA at a dose of 1.5 mg/kg /day or more was higher than those treated at a dose less than 1 mg/kg/day(P< 0.05), The incident of adverse reaction in patients who were older than 45 was higher than those under the age of 45 years.All the adverse reaction self-recovered or recovered under proper treatment.There are no irreversible and fatal cases in this study. We only found that a young woman with crohn’s disease after one-year treatment was diagnosed with ovarian mucous adenocarcinoma and had a surgical treatment.Conclusions:The adverse reactions and drug-withdraw rate of IBD patients treated by AZA were quite high, and the clinical manifestation of AZA was varied, usually being seen in myelotoxicity and abnormal liver function,but it’not so severe and is reversible after stopping the drug or treatment. We should pay special attention to monitoring its side effects at the beginning of therapy, specially during the first three months, meanwhile we should never ignore the late-onset adverse reactions. This study found one malignant tumor, no cases of secondary lymphoma. Agranulocytosis, pancreatitis and some infection of specific pathogen may affect the prognosis of patients, therefore the clinicians must pay attention to it. They should also screen special diseases before the drug, reinforce the monitor after the drug, pay close attention to the high risk patients and deal with the adverse reactions properly to improve the prognosis. The study also discovered the risk of leukopenia increases in patients who added 5-ASA and treated with AZA at a higher dosage, the risk of adverse reaction increases in patients who get older and treated with AZA at a higher dosage.